NM_000038.6(APC):c.4669A>G (p.Ile1557Val) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 23, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000589170.2

Allele description [Variation Report for NM_000038.6(APC):c.4669A>G (p.Ile1557Val)]

NM_000038.6(APC):c.4669A>G (p.Ile1557Val)

Gene:
APC:APC regulator of WNT signaling pathway [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5q22.2
Genomic location:
Preferred name:
NM_000038.6(APC):c.4669A>G (p.Ile1557Val)
HGVS:
  • NC_000005.10:g.112840263A>G
  • NG_008481.4:g.152743A>G
  • NM_000038.6:c.4669A>GMANE SELECT
  • NM_001127510.3:c.4669A>G
  • NM_001127511.3:c.4615A>G
  • NM_001354895.2:c.4669A>G
  • NM_001354896.2:c.4723A>G
  • NM_001354897.2:c.4699A>G
  • NM_001354898.2:c.4594A>G
  • NM_001354899.2:c.4585A>G
  • NM_001354900.2:c.4546A>G
  • NM_001354901.2:c.4492A>G
  • NM_001354902.2:c.4396A>G
  • NM_001354903.2:c.4366A>G
  • NM_001354904.2:c.4291A>G
  • NM_001354905.2:c.4189A>G
  • NM_001354906.2:c.3820A>G
  • NP_000029.2:p.Ile1557Val
  • NP_001120982.1:p.Ile1557Val
  • NP_001120983.2:p.Ile1539Val
  • NP_001341824.1:p.Ile1557Val
  • NP_001341825.1:p.Ile1575Val
  • NP_001341826.1:p.Ile1567Val
  • NP_001341827.1:p.Ile1532Val
  • NP_001341828.1:p.Ile1529Val
  • NP_001341829.1:p.Ile1516Val
  • NP_001341830.1:p.Ile1498Val
  • NP_001341831.1:p.Ile1466Val
  • NP_001341832.1:p.Ile1456Val
  • NP_001341833.1:p.Ile1431Val
  • NP_001341834.1:p.Ile1397Val
  • NP_001341835.1:p.Ile1274Val
  • LRG_130:g.152743A>G
  • NC_000005.9:g.112175960A>G
  • NM_000038.5:c.4669A>G
Protein change:
I1274V
Links:
dbSNP: rs763578917
NCBI 1000 Genomes Browser:
rs763578917
Molecular consequence:
  • NM_000038.6:c.4669A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127510.3:c.4669A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127511.3:c.4615A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354895.2:c.4669A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354896.2:c.4723A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354897.2:c.4699A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354898.2:c.4594A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354899.2:c.4585A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354900.2:c.4546A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354901.2:c.4492A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354902.2:c.4396A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354903.2:c.4366A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354904.2:c.4291A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354905.2:c.4189A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354906.2:c.3820A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000292773GeneDxcriteria provided, single submitter
Uncertain significance
(Nov 23, 2018)
germlineclinical testing

Citation Link,

SCV000694056Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Jul 1, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.

Huang J, Löhr JM, Nilsson M, Segersvärd R, Matsson H, Verbeke C, Heuchel R, Kere J, Iafrate AJ, Zheng Z, Ye W.

Clin Chem. 2015 Nov;61(11):1408-16. doi: 10.1373/clinchem.2015.238543. Epub 2015 Sep 16.

PubMed [citation]
PMID:
26378065

Details of each submission

From GeneDx, SCV000292773.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted APC c.4669A>G at the cDNA level, p.Ile1557Val (I1557V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Ile1557Val was observed at an allele frequency of 0.02% (19/125688) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ile1557Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694056.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: The APC c.4669A>G (p.Ile1557Val) variant involves the alteration of a non-conserved nucleotide, which is not located in any known domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 14/120490 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001962 (13/66264). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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